A class of proteins now have been identified that are competent to act as true chondrogenic tissue morphogens, able, on their own, to induce the proliferation and differentiation of progenitor cells into functional bone, cartilage, tendon, and/or ligamentous tissue. These proteins, referred to herein as "osteogenic proteins" or "morphogenic proteins" or "morphogens," includes members of the family of bone morphogenic proteins (BMPs) which were initially identified by their ability to induce ectopic, endochondral bone morphogenesis. The osteogenic proteins generally are classified in the art as a subgroup of the TGF-.beta. superfamily of growth factors (Hogan (1996) Genes & Development 10:1580-1594). Members of the morphogen family of proteins include the mammalian osteogenic protein-1 (OP-1, also known as BMP-7, and the Drosophila homolog 60A), osteogenic protein-2 (OP-2, also known as BMP-8), osteogenic protein-3 (OP-3), BMP-2 (also known as BMP-2A or CBMP-2A, and the Drosophila homolog DPP), BMP-3, BMP-4 (also known as BMP-2B or CBMP-2B), BMP-5, BMP-6 and its murine homolog Vgr-1, BMP-9, BMP-10, BMP-11, BMP-12, GDF3 (also known as Vgr2), GDF8, GDF9, GDF10, GDF11, GDF12, BMP-13, BMP-14, BMP-15, GDF-5 (also known as CDMP-1 or MP52), GDF-6 (also known as CDMP-2), GDF-7 (also known as CDMP-3), the Xenopus homolog Vgl and NODAL, UNIVIN, SCREW, ADMP, and NEURAL. Members of this family encode secreted polypeptide chains sharing common structural features, including processing from a precursor "pro-form" to yield a mature polypeptide chain competent to dimerize, and containing a carboxy terminal active domain of approximately 97-106 amino acids. All members share a conserved pattern of cysteines in this domain and the active form of these proteins can be either a disulfide-bonded homodimer of a single family member, or a heterodimer of two different members (see, e.g., Massague (1990) Annu. Rev. Cell Biol. 6:597; Sampath, et al. (1990) J. Biol. Chem. 265:13198). See also, U.S. Pat. No. 5,011,691; U.S. Pat. No. 5,266,683, Ozkaynak et al. (1990) EMBO J. 9:2085-2093, Wharton et al. (1991) PNAS 88:9214-9218), (Ozkaynak (1992) J. Biol. Chem. 267:25220-25227 and U.S. Pat. No. 5,266,683); (Celeste et al. (1991) PNAS 87:9843-9847); (Lyons et al. (1989) PNAS 86:4554-4558). These disclosures describe the amino acid and DNA sequences, as well as the chemical and physical characteristics of these osteogenic proteins. See also Wozney et al. (1988) Science 242:1528-1534); BMP 9 (WO93/00432, published Jan. 7, 1993); DPP (Padgett et al. (1987) Nature 325:81-84; and Vgl (Weeks (1987) Cell 51:861-867).
Thus, true osteogenic proteins capable of inducing the above-described cascade of morphogenic events that result in endochondral bone formation have now been identified, isolated, and cloned. Whether naturally-occurring or synthetically prepared, these osteogenic factors, when implanted in a mammal in association with a conventional matrix or substrate that allows the attachment, proliferation and differentiation of migratory progenitor cells, have been shown to induce recruitment of accessible progenitor cells and stimulate their proliferation, thereby inducing differentiation into chondrocytes and osteoblasts, and further inducing differentiation of intermediate cartilage, vascularization, bone formation, remodeling, and finally marrow differentiation. Furthermore, numerous practitioners have demonstrated the ability of these osteogenic proteins, when admixed with either naturally-sourced matrix materials such as collagen or synthetically-prepared polymeric matrix materials, to induce bone formation, including endochondral bone formation under conditions where true replacement bone otherwise would not occur. For example, when combined with a matrix material, these osteogenic proteins induce formation of new bone in: large segmental bone defects, spinal fusions, and fractures. Without exception, each of the above-referenced disclosures describes implantation or delivery of the osteogenic protein at the defect site by packing, filling, and/or wrapping the defect site with an admixture of osteogenic protein and matrix, with the relative volume and surface area of matrix being significant. In the case of non-union defects which do not heal spontaneously, it has heretofore been conventional practice to implant volumes of matrix-osteogenic factor admixtures at the defect site, the volumes being sufficient to fill the defect in order to provide a 3-dimensional scaffold for subsequent new bone formation. While standard bone fractures, can heal spontaneously and without treatment, to the extent the art has contemplated treating fractures with osteogenic proteins, it has been the practice in the art to provide the osteogenic protein together with a matrix locally to a defect site to promote healing.
While implanting a volume of matrix may be conventional wisdom, particularly in the case of non-healing non-union defects, clinical consequences may develop in certain patients as a result of this practice. For example, patients undergoing repeated constructions or defect repairs, or wherein the matrix volume is large, can develop adverse immunologic reactions to matrices derived from collagen. Collagen matrices can be purified, but residual levels of contaminants can remain which is strongly allergenic for certain patients. Alternatively, demineralized autogenic, allogenic or xenogenic bone matrix can be used in place of collagen. Such a matrix is mechanically superior to collagen and can obviate adverse immune reactions in some cases, but proper preparation is expensive, time consuming and availability of reliable sources for bone may be limited. Such naturally-sourced matrices can be replaced with inert materials such as plastic, but plastic is not a suitable substitute since it does not resorb and is limited to applications requiring simple geometric configurations. To date, biodegradable polymers and copolymers have also been used as matrices admixed with osteogenic proteins for repair of non-union defects. While such matrices may overcome some of the above-described insufficiencies, use of these matrices still necessitates determination and control of features such as polymer chemistry, particle size, biocompatability and other particulars critical for operability.
In addition, individuals who, due to an acquired or congenital condition, have a reduced ability to heal bone fractures or other defects that normally undergo spontaneous repair would benefit from methods and injectable compositions that can enhance bone and/or cartilage repair without requiring a surgical procedure. Finally, an injectable formulation also provides means for repairing osteochondral or chondral defects without requiring a surgical procedure.
Needs remain for devices, implants and methods of repairing bone defects which do not rely on a matrix component. Particular needs remain for devices, implants and methods which permit delivery of bone-inducing amounts of osteogenic proteins without concomitant delivery of space-filling matrix materials which can compromise the recipient and/or fail to be biomechanically and torsionally ideal. Needs also remain for providing methods and devices, particularly injectable devices that can accelerate the rate and enhance the quality of new bone formation.
Accordingly, it is an object of the instant invention to provide devices, implants and methods of use thereof for repairing bone defects, cartilage defects and/or osteochondral defects which obviate the need for an admixture of osteogenic protein with matrix. The instant invention provides matrix-free osteogenic devices, implants and methods of use thereof for repairing non-healing non-union defects, as well as for promoting enhanced bone formation for spinal fusions and bone fractures, and for promoting articular cartilage repair in chondral or osteochondral defects. These and other objects, along with advantages and features of the invention disclosed herein, will be apparent from the description, drawings and claims that follow.